1. Field of the Invention
The present invention relates to a preventive or therapeutic agent for inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. In particular, the present invention relates to a pharmaceutical composition for preventing or treating inflammatory bowel diseases, comprising 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzoazepine, a prodrug thereof or a pharmaceutically acceptable salt thereof, or 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzoazepine or a pharmaceutically acceptable salt thereof.
2. Background Art
Inflammatory bowel disease (referred to hereinafter as “IBD”) indicates idiopathic chronic persistent type non-specific enteritis, that is, typical diseases including ulcerative colitis, Crohn's disease (Koji Uraushibara, Mamoru Watanabe: “Concept, Definition and Epidemiology of Inflammatory Bowel Diseases”; Inflammatory Bowel Diseases, pp. 9-15, 2005, Ed. Norihumi Hibi; Saishin-Igaku (Reference 1). IBD is considered as a disease that the immunity mechanism of intestinal mucosa is collapsed by some etiologies to cause the excessive reaction with enterobacterium flora and bacterial components, which develops and sustains enteritis. However, the etiology of the disease has not been specified. It is known that in ulcerative colitis and Crohn's disease, which are the main diseases involved in IBD, the active phase in which symptoms such as ulceration and bleeding are expressed and the remission phase in which symptoms are remitted or ameliorated appear repeatedly, and it is believed that these diseases may recur over 10 to 20 years.
The critical mechanism of IBD has not been thoroughly elucidated yet.
Although allergy and infection theories were proposed for the explanation of the critical mechanism in the past, IBD is now considered as an autoimmune disease and studies which give support to the autoimmune theory including, for example, that the disease is accompanied with increased anti-neutrophil IgG antibody in blood have increased (Hibi N., Introduction Japanese J. Clin. Med., 63(5): 741-743, 2005 (Reference 2); Keiichi Mitsuyama, Makoto Toyonaga, and Michio Sata, “Pathology and Pathophysiology of Inflammatory Bowel Diseases”; Inflammatory Bowel Diseases, pp. 28-36, 2005, Ed. Norihumi Hibi; Saishin-Igaku (Reference 3). On the other hand, Ishizaka et al. have confirmed in 1966 the presence of the IgE antibody which is a causal antibody of allergy and demonstrated that the allergic reaction is a histamine releasing reaction mediated by the antigen specific IgE antibody (Mechanism of Body and Allergy, 1998 Shuichi Ueno, Nippon Jitsugyo Publishing (Reference 4); and Ishizaka K., Ishizaka T, and Hornbrook M M. Physico-Chemical Properties of Human Reaginic Antibody IV: Presence of a Unique Immunoglobulin as a Carrier of Reaginic Activity. Journal of Immunology, 97 (1): 75-85, 1966 (Reference 5)). Thus, the allergy theory in IBD that the production of antigen-specific IgE antibody had not been observed became negative. It has also been confirmed that disodium cromoglycate (DSCG; Akihide Koda, “History and Present Situation of Anti-allergic Agents”, pp. 32-39, 1988, Ed. Terumasa Miyamoto, Hiroshi Baba and Minoru Okuda, Life Science Co., Ltd. (Reference 6)), which was commonly approved as a typical histamine release inhibitor in three regions of Japan, United States of America and Europe, is ineffective against IBD (Crotty B and Jewell D P. Drug therapy of ulcerative colitis. Br. J. Clin. Pharmc. 34(3): 189-198, 1992 (Reference 7); Binder V, Elsborg L, Greibe J, Hendriksen C, Hoj L, Jensen K B, Kristensen E, Madsen J R, Marner B, Riis P, and Willumsen L. Disodium cromoglycate in the treatment of ulcerative colitis and Crohn's disease. 22 (1): 55-60, 1981 (Reference 8); and, Buckell N A, Gould S R, Day D W, Lennard-Jones J E, and Edwards A M. Controlled trial of disodium cromoglycate in chronic persistent ulcerative colitis. Gut, 19 (12): 1140-1143. 1978 (Reference 9)).
Under these circumstances, it has now generally been recognized that the allergic reaction is involved only seldom in critical mechanism of IBD both in clinical and basic studies.
Furthermore, it has recently been reported that inflammatory enteritis similar to IBD is spontaneously developed in IL-2 knockout mice and IL-10 knockout mice (Ma A, Datta M, Margosian E, Chen K and Horak I. T cells, but not B cells, are required for bowel inflammation in interleukin-2-deficient mice, J. Exp. Med. 182 (5): 1567-1572, 1995 (Reference 10); and, Kuhn R, Lohler J, Rennick D, Rajewsky K and Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell, 75(2): 263-274, 1993 (Reference 11)). The importance of abnormality of T cell-mediated immune reaction in manifestation of the disease has been indicated by the evidences that the defect of IL-2 having the T cell proliferating activity or IL-10 as a typical inhibitory cytokine caused IBD-like enteritis. That is, the crisis of enteritis is prevented in normal intestine by proliferating and activating T cells which suppress immune response against substances recognized as nonself including proteins derived from foods and foreign bodies derived from normal bacterial flora. However, it is considered that a certain immune system in topical intestinal mucosa is collapsed for some reason, which makes immune response uncontrollable to foreign bodies such as intestinal bacterial flora to which immune response is originally suppressed (Ohkusa T, Nomura T and Sato N., The role of bacterial infection in the pathogenesis of inflammatory bowel disease., International Medicine, 43(7): 534-539, 2004 (Reference 12), thus leading to the development of IBD. It is generally believed as described above that the immune abnormality centering around T cells is intensely involved in the critical mechanism of IBD (Tadao Baba, inflammatory bowel diseases, Recent Trend. Matsushita Medical Journal 39(1): 1-14, 2000 (Reference 13)).
Therapeutic object of IBD consists of induction of remission (alleviation of symptoms in the active phase) and preventing recurrence. While the therapeutic guidelines in respective countries do not reach complete consensus, a curative treatment commonly recommended in Japanese, US and British guidelines is as follows:
That is, 5-aminosalicylic acid (5-ASA) or sulfasalazine, which depends on the type, site and severity of disease of each patient, is employed as a standard therapeutic agent in treatment of mild to moderate patients. 5-ASA is a decomposition product of sulfasalazine and is believed the active substance of sulfasalazine. To moderate or severe patients, a steroid for oral or rectal dosage is also administered in addition to 5-ASA and sulfasalazine. In severe cases, remission is induced by the intravenous injection of steroid or an immune inhibitor cyclosporine. In recent years, the treatment with an anti-TNF-a-antibody and the like has been also carried out. 5-ASA and sulfasalazine are recommended for preventing recurrence after the induction of remission. Also, immunosuppressants such as azathiopurine (AZA) or 6-mercaptopurine (6-MP) are recommended for the prevention of recurrence.
However, 5-ASA and sulfasalazine widely used for the treatment of IBD often show insufficient therapeutic effects in moderate and severe patients. In such cases, remission is induced by using an immune inhibitor such as steroids or cyclosporine in serious patients in order to control abnormal reactions mainly caused by T cells, which are involved in the condition and severity of the diseases. Surgical excision of large intestine is performed on patients in refractory state in whom the induction of remission with these agents is difficult. It is known that if the treatment for preventing the recurrence is not performed after the induction of remission, that is, after the inflammation of the digestive tract has been ameliorated, IBD recurs or recrudesces in 70% of the patients. Therefore, it is also recommended in the guidelines to maintain the remission state (maintenance of remission) by continuing the prophylactic treatment for the recurrence. While the administration of 5-ASA or sulfasalazine is recommended for the maintenance of remission (prevention of recurrence), AZA or 6-MP is employed in the case that satisfactory effects are not obtained with 5-ASA or sulfasalazine. However, AZA and 6-MP require several months for the onset of effect, thus leaving the problem to be solved in their effectiveness.
Furthermore, the therapeutic agents such as steroids, cyclosporine, AZA or 6-MP exhibit strong systemic side effects, and thus there is a limitation on the use of them. By way of example, in addition to the side effects relating to immunodeficiency; steroids suppress osteogenesis or growth particularly in hebetic patients; cyclosporines cause renal disorders; AZA and 6-MP cause influenza-like symptoms and serious side effects such as bone marrow inhibition and hepatopathy. In addition, teratogenicity has been reported in animal experiments with steroids, cyclosporine, AZA and 6-MP, and thus safety in pregnancy and lactation has not been established, which limits the administration to female patients of the late teens to twenties who are predisposed to the development of IBD.
Under the circumstances described above, there has been in therapeutic fields a need for developing a novel drug for prophylactic treatment of inflammatory bowel diseases which can be safely and strongly induced into remission and used also in maintenance therapy for a long period of time.
2-(1-Isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzoazepine (referred to hereinafter as “Compound A”), and 7,8-dimethoxy-4(5H),10-dioxo-1H-1,2,3-triazolo[4,5-c][1]benzoazepine (referred to hereinafter as “Compound B”) have the structures represented in the following:

It is known that Compound A is a prodrug of Compound B and is rapidly converted into Compound B in the body after permeating through various mucosae including digestive tracts, thus expressing histamine release inhibitory effect (see WO 95/18130 (JP 3,290,664-B, U.S. Pat. No. 5,686,442)). It has also been revealed that Compound A has an improved absorbability seven times as large as that of Compound B upon oral administration (see WO 99/16770 (JP 3,188,482-B, U.S. Pat. No. 6,372,735)).
However, the literature relates to the therapeutic or prophylactic agents of allergic diseases and provides or indicates none of inflammatory bowel diseases (IBD), which are believed to have little relationship with allergic diseases, or their prophylactic or therapeutic methods. Thus, no disclosure is necessarily found in examples.